Optimal inhibition of the immune response to destroy transplanted organs in clinical transplantation has yet to be achieved. Therefore, transplant recipient patients continue to experience problems with rejection of their transplants as well as the side effects of the non-specific immunosuppressive strategies which are required to maintain these transplants which include an increased incidence of both infections and malignancies. T lymphocytes play an important role in transplant rejection. The B7/CD28 signaling pathway has been shown to be important for effective T cell activation. Previous studies in rodent models have demonstrated that blockade of this pathway with a reagent called CTLA4-Ig can effectively prolong the survival of transplanted organs. The aim of this study was to test the hypothesis that CTLA4-Ig will prolong the survival of renal transplants in a nonhuman primate model. The demonstration of this effect would facilitate the application of this reagen t to prevent graft rejection in clinical transplantation. Renal transplants were performed in rhesus macaques to test 3 specific CTLA4-Ig treatment protocols. 1) CTLA4-Ig alone initiated at the time of transplant; 2) CTLA4-Ig alone initiated 2 days after transplant; and 3) CTLA4-Ig combined with cyclosporine and prednisone initiated at the time of transplants. The results to date indicate that a short course of CTLA4-Ig treatment alone at the time of transplant was associated with marked prolongation of allograft survival in one of four recipients. Delaying the initiation of CTLA4-Ig treatment did not appear to improve survival. A 16-day course of CTLA4-Ig combined with cyclosporine and prednisone prolonged renal allograft survival but not indefinitely. Extension of this triple immunosuppressive therapy to 13 weeks after transplant was associated with increased survival. In summary, CTLA4-Ig is immunosuppressive in the nonhuman primate renal allograft model.